This invention relates to fused heterocyclic ring systems in which a quinoline, a naphthalene or a pyridine ring system is fused to a 2-methyl-, 2-ethyl, or 2-acetyl pyridimidine-4(3H)-one or to a pyrimidine-2-carboxylic acid 4(3H)-one or a derivative thereof, and their use as anti-allergy agents. More particularly, it relates to 2-alkylpyrimido[4,5-b]quinolin-4-(3H)-ones, 2-alkylpyrido[4,5-b]pyrimidon-4(3H)-ones wherein alkyl is methyl or ethyl, and the corresponding 2-acetyl derivatives, pyrimido[4,5-b]quinolin-4(3H)-ones-2-carboxylic acids, benzo[g]quinazolin-4(3H)-one-2-carboxylic acids, and pyrido[2,3-d]pyrimidin-4(3H)-one-2-carboxylic acids; esters, amides, and pharmaceutically-acceptable salts thereof which are useful as inhibitors of allergic reactions, and especially of allergic bronchial asthma.
A number of pyrimido[4,5-b]quinolines (1,3-diazo-acridines) are described in the art (J. Chem. Soc., 727 (1927); J. Hetero. Chem. 7, 99 (1970); J. Am. Chem. Soc. 78, 5108 (1956); and J. Chem. Soc., 552 (1948). However, none of them contain a carboxy group or functional derivative thereof, i.e., an ester, amide, acid chloride, with the exception of 2,4-dihydroxy-pyrimido[4,5-b]quinoline-5-carboxylic acid, its methyl ester, amide and acid chloride; 1,3-dimethyl-1,2,3,4-tetrahydro-pyrimido[4,5-b]quinolin-2,4-dione-5-carbox ylic acid methyl ester; and 10-methyl-2,3,4,10-tetrahydro-pyrimido[4,5-b]quinolin-2,4-dione-5-carboxyl ic acid and its methyl ester. The products were investigated as potential riboflavin antagonists, Taylor et al., J. Am. Chem. Soc. 78, 5108 (1956) describe 2-methylpyrimido[4,5-b]quinolin-4(3H)-one. No 2-carboxy substituted derivatives are described in the literature.
The known pyrimido[4,5-b]quinolin-4(3H)-one when tested by the passive cutaneous anaphylaxis (PCA) test described herein affords only 33% protection in rats at 3.0 mg./kg. via the intravenous route of administration. It is, relative to the compounds of this invention, of marginal value as an anti-allergy agent.
In the benzo[g]quinazolin-4(3H)-one series of compounds of formula II, no analogs wherein a carboxy group (or an ester or amide thereof) is attached directly to the nucleus appear to have been described in the art. However, 2-carbethoxymethylbenzo[g]quinazolin-4(3H)-one is described by Reid et al., Ber. 96, 1216 (1963). No utility is reported for the compound It afforded 49% protection in the PCA test when administered intravenously at 3.0 mg./kg. Upon acid hydrolysis it undergoes facile decarboxylation at room temperature to 2-methylbenzo[g]quinazolin-4(3H)-one (Reid et al., Ber. 95, 3042, 1962) which shows little or no activity in the PCA test.
Benzo[g]quinazolin-4(3H)-one, the compound related to formula II, is reported in Indian Pat. No. 74,146, March 2, 1963 [C.A. 60, 1773f, 1964] to be active as a bronchodilator. When tested in the PCA test described below it was observed to provide 31% protection in rats at 3.0 mg./kg. by the intraveneous route of administration. It is, at best, of marginal value in the treatment of bronchial allergies.
The preparation of pyrido[2,3-d]pyrimidines containing a 5-carboxy or 5-carbalkoxy group is described by Fatutta, Cazz. Chom. Ital. 93, (5), 576-84 (1963); C.A. 59, 6401 (1963). No utility is reported for the products. Mulvey et al., J. Org. Chem. 29, 2903-7 (1964) report the synthesis of pyrido[2,3-d]pyrimidines having a 6-carboxy, 6-carboxamido, or 6-carbalkoxy group. No reports of pyrido[2,3-d]pyrimidin-4(3H)-one-2-carboxylic acids, esters, or amides of formula III below appear in the literature. The preparation of 2-methylpyrido[2,3-d]pyrimidin-4(3H)-one and its use as a saluretic and circulatory stimulating agent is described in South African Patent 6902561, granted October 21, 1969 (C.A. 72, 125071s, 1970).
Allergic reactions, the symptoms resulting from an antigen antibody interaction, manifest themselves in a wide variety of ways and in diffusely different organs and tissues. One of the most disabling and debilitating of the allergic reactions is asthma, a functional condition of the bronchi characterized by periodic and spasmodic attacks of breathlessness, wheezing, coughing, and expectoration of mucous.
Efforts to discover medicinal agents to alleviate the symptoms of the abnormal physiologic state have been extensive. As early as 1910, Metthews, Brit. Med. J., 1, 441 (1910) reported the bronchodilator effects of epinephrine. Since then, Chen and Schmidt, J. Pharmacol. Exper. Therap., 24, 339 (1924) reported the use of the alkaloid ephedrine as an orally efficacious bronchodilator with the same spectrum of activity as epinephrine. In 1940, Konzett, Arch. Exp. Path. Pharmak. 197, 27 (1940) outlined the effects of the potent aerosol bronchodilator isoproterenol. Cullum et al., Brit. J. Pharmacol. Exp. 35, 141 (1969) reported the pharmacology of solbutamol, a potent bronchodilator of prolonged duration, and active via both oral and aerosol administration. Many bronchodilator preparations contain theopylline. These are generally less potent than the sympathomimetic amines such as isoproterenol and solbutamol, and are ineffective in aerosol administration.
Recently, Cox and co-workers, Adv. in Drug Res., 5, 115 (1970) described the pharmacology of disodium cromoglycate [1,3-bis-(2-carboxychromon-5-yloxy)-2-hydroxypropane, Intal], an agent useful in the treatment of bronchial asthma. It is not a bronchodilator but mediates its therapeutic effects by a unique mechanism of action. It suffers from the lack of oral efficacy and, for optimum results, is administered by inhalation as a solid inhalant.
Although the aforementioned agents represent outstanding contributions toward the treatment of asthma, many of them exert the undesired side effect of cardiac stimulation.